Abstract
The proteasome inhibitor bortezomib is effective in hematologic malignancies such as multiple myeloma but has little activity against solid tumors, acts covalently, and is associated with undesired side effects. Therefore, noncovalent inhibitors that are less toxic and more effective against solid tumors are desirable. Structure activity relationship studies led to the discovery of PI-1840, a potent and selective inhibitor for chymotrypsin-like (CT-L) (IC50 value = 27 ± 0.14 nm) over trypsin-like and peptidylglutamyl peptide hydrolyzing (IC50 values >100 μm) activities of the proteasome. Furthermore, PI-1840 is over 100-fold more selective for the constitutive proteasome over the immunoproteasome. Mass spectrometry and dialysis studies demonstrate that PI-1840 is a noncovalent and rapidly reversible CT-L inhibitor. In intact cancer cells, PI-1840 inhibits CT-L activity, induces the accumulation of proteasome substrates p27, Bax, and IκB-α, inhibits survival pathways and viability, and induces apoptosis. Furthermore, PI-1840 sensitizes human cancer cells to the mdm2/p53 disruptor, nutlin, and to the pan-Bcl-2 antagonist BH3-M6. Finally, in vivo, PI-1840 but not bortezomib suppresses the growth in nude mice of human breast tumor xenografts. These results warrant further evaluation of a noncovalent and rapidly reversible proteasome inhibitor as potential anticancer agents against solid tumors.
Highlights
Food and Drug Administration-approved proteasome inhibitors act covalently, which hampers their safety
Approval by the Food and Drug Administration of bortezomib further validated targeting the proteasome for the development of anticancer drugs
Carfilzomib, a more recently approved proteasome inhibitor, appears to be more active against liquid tumors. it has not been tested as thoroughly as bortezomib against solid tumors. These drawbacks could be due at least in part to the fact that bortezomib inhibits the CT-L activity of the proteasome by binding covalently to threonine 1 of the -5 subunit of the proteasome. This suggestion needs to be further supported with more direct evidence, the development of noncovalent proteasome inhibitors to determine whether they lack these drawbacks is highly desirable
Summary
Food and Drug Administration-approved proteasome inhibitors act covalently, which hampers their safety. Results: Structure activity relationship (SAR) studies, mass spectrometry, and dialysis identified PI-1840 as a noncovalent proteasome inhibitor that sensitizes human cancer cells to p53 and Bcl antagonists. In vivo, PI-1840 but not bortezomib suppresses the growth in nude mice of human breast tumor xenografts These results warrant further evaluation of a noncovalent and rapidly reversible proteasome inhibitor as potential anticancer agents against solid tumors. In contrast to normal cells, cancer cells generally have higher levels of proteasome activity [3] and have acquired a series of mutations that render them dependent on strong activation of survival pathways [10] One of these is the phosphorylation-dependent recognition and subsequent degradation of cellular proteins by the UPS. We describe the development of a novel noncovalent chemical probe, PI-1840, and provide data that give further support to the notion that noncovalent inhibitors are more effective against solid tumors
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